8 - Neurodegenerative Diseases Flashcards
Alzheimer’s
- a type of Dementia, accounting for 62%
- progressive loss of structure and function of neurons
> huge volume loss - particularly in the frontal and temporal areas of the brain (hence associated with language symptoms)
- hippocampus is particularly affected (hence the memory loss and cognition loss)
Prevalence:
- 1 in 80 (500,000)
Incidence:
- 1 in 20 (125,000)
- only around 44% of people with dementia are diagnosed
- more common in women
Symptoms:
- memory loss
- poor face recognition
- disorientation
- poor judjement
- misplacing things
- personality changes
- particular loss of Cholinergic neurons
- unclear why
Incidence and Prevalence
Incidence:
- total number of cases in an area
Prevalence:
- number of new cases in an area in 1 year
Cellular pathology in AD
Between the cells:
- amyloid plaques formed from Beta Amyloid, which is formed from Amyloid Precursor Protein
Within Cells:
- Neurofibrillary Tangles made of Tau protein
Amyloid Precursor Protein (APP)
- coded for by Chromosome 21
- normal function is unclear, but potentially:
> synapse formation / neuronal plasticity / iron regulation - Amyloid Precursor Protein lies partly within and partly out of the cell, and is acted on by 3 secretases:
> alpha-secretase
> beta-secretase
> gamma-secretase - the amounts of these enzymes dictates whether APP will be broken down to Beta Amyloid (and thus amyloid plaques)
Healthy APP pathway:
- alpha-secretase cleaves APP so one part is left inside the cell and one part outside
- gamma-secretase cleaves the membrane segment of what is left of APP into two smaller segments
- none of these products are harmful
Alzheimer’s APP pathway:
- beta-secretase cleaves APP at a location different to alpha- (one part of APP is left inside and one outside)
- gamma-secretase then cleaves the membrane segment of what’s left into two segments, one of which is Beta-Amyloid
> Beta-Amyloid can range from 39-43 amino acids, the longer chains are more likely to form plaques
+ Beta-Amyloid leaves the cell and forms clumps of Oligomers, which clump together to form plaques
Both of these pathways occur, but the Amyloid pathway can have an increased likelihood due to:
- mutations in APP gene or Presenilin 1 and 2 (related to gamma-secretase
- failure in the mechanism to clear beta-secretase due to ApoE4 gene
Neurofibrillary Tangles
- normal Tau proteins stabilise the microtubules of cells by binding to 4 points on the microtubule and allows for effective transport
- if Tau becomes hyperphosphorlyated, it cannot bind to the microtubules (phosphotau)
- microtubules become unstable and transport ceases, ultimately causing axon structure issues and problems with synapses (due to lack of NT)
Hypotheses for AD
- Tau hypothesis
- Amyloid hypothesis
- Unknown trigger hypothesis
> an unknown trigger initiates both tau and amyloid pathways
Amyloid Hypothesis
Amyloid Hypothesis:
- caused by:
> Trisomy 21
> Presenilin 1 & 2 mutations (affecting gamma-secretase)
> ApoE4 mutation (preventing beta-secretase removal)
- produces:
> beta-amyloid oligomers which form clumps which form beta-amyloid plaques
+ in limbic cortices - causes:
> synaptic dysfunction
> neuroinflammation (glial cells) which leads to neurofibrillary tangles - leads to:
> widespread neuronal dysfunction
Problems:
- there is a weak correlation between the presence of beta-amyloid and neurodegeneration
Tau Hypothesis
- tau hyperphosphorylation causes forms neurofibrillary tangles which destroy the neuron
- tau oligomers are then released, causing an inflammation reaction which causes beta-amyloid to form
Evidence:
- AD severity correlates well with accumulation of Neurofibrillary Tangles (NFTs)
> and with hyperphosphorylated Tau
- decrease in Tau filaments due to drugs that alleviate cognitive impairment
Risk factory for Alzheimer’s disease
- smoking
- drinking
- no exercise
- no human contact
- low intellectual activity
Treating Alzheimer’s disease
Cholinesterase Inhibitors
- inhibit the action of AChE (which breaks down ACh)
- benefit in mild-moderate Alzheimer’s
- reduces anxiety, improves memory and concentration and daily task ability
- side effects: > low appetite > nausea / vomiting > insomnia > diarrhoea > dizziness / headaches > cramps
NMDA receptor antagonist
- blocks the effect of Glutamate on NMDA receptors
- used in severe AD and moderate AD but only when unresponsive to AChEIs
- slows symptom progression and helps with disorientation, delusions and daily tasks
- side effects > dizziness > headaches > tiredness > raised blood pressure > constipation
Antipsychotic drugs
- make them easier to handle
- very controversial
Parkinson’s Disease
- second most common neurodegenerative disease Prevalence: - 120,000 - 25% higher in men Incidence: - 10,000
Motor Symptoms:
- rigidity and trembling of the head and extremeties
- forward tilt of trunk
- shuffling gait
- reduced arm swimging
- reduced facial expressions
Non-motor Symptoms:
- impaired memory
- fluctuating attention
- mood problems
- increased likelihood of dementia
Pathology of Parkinson’s
- loss of dopaminergic neurons
- primarily (80% loss of neurons) in the Nigrostriatal Pathway
> from the Substantia Nigra pars Compacta to the Dorsal Striatum - secondary loss (50%) of the Mesolimbic and Mesocortical Pathways
> from the Ventral Tegmental area to Nucleus Accumbens / Prefrontal Cortex
Also:
- the presence of abnormal cellular inclusions called Lewy Bodies
Cortical Loops in the Basal Ganglia
- from the cortex
- to the Striatum (basal ganglia input) [also dopamine input]
- to Globus Pallidus and Substantia Nigra pars Reticulata (basal ganglia output)
- to the Thalamus
> back to the cortex
4 loops (thus functions):
- Limbic
- Associative
- Sensory
- Motor
Direct Pathway:
- Cortex excites the Striatum
- Substantia Nigra pars compacta (SNc) sends Dopamine to the Striatum via D1 Receptors, which excites the Striatum further
- activation of D1 Receptors increases the Striatum driven inhibition of Globus Pallidus - internal (GPi) and Substantia Nigra pars reticulata (SNr)
- this inhibition of GPi and SNr means less inhibition of the Thalamus
- which means enhanced excitation of the Cortex by the Thalamus
THUS:
- loss of Dopamine means less Striatum excitement, less inhibition of GPi and SNr, more inhibition of the Thalamus, and less excitation of the Cortex
Indirect Pathway:
- Cortex excites the Striatum
- SNc sends Dopamine to the Striatum via D2 Receptors, which reduces excitation of the Striatum
- activation on D2 Recptors decreases the Striatum driven inhibition of the Globas Pallidus External (GPe)
- which causes increased inhibition of the Subthalamic Nucleus (STN)
- which causes decreased excitation in the GPi and SNr
- which causes decreased inhibition of the Thalamus, and therefore enhanced excitation of the Cortex
THUS:
- loss of Dopamine means more Striatum excitation, more inhibition of the GPe, less inhibition of the STN, more excitation of the GPi and SNr, more inhibition of the Thalamus and thus less excitation of the Cortex
Causes of Dopaminergic Neurodegeneration
Genetic:
- various, including Park1 (codes for the peptides in Lewy Bodies)
Stress:
- oxidative stress = imbalance of production of reactive oxygen species (ROS) and their clearance
- excess ROS causes damage to DNA, lipids and proteins
- DA neurons are 4x more susceptible to ROS damage
Environmental:
- toxins
- pesticides
Treating PD
Increasing Dopamine Levels: - we can: > increase production > increase release > mimic the action (agonist) > decrease reuptake > decrease breakdown
- since Tyrosine Hydroxylase is the rate-limiting step in Dopamine production, tablets of L-DOPA are given
- but so that the L-DOPA reaches the brain before it is converted to Dopamine, it is attached to a Dopa Decarboxylase Inhibitor
- when this pair reaches the Blood Brain Barrier, the L-DOPA can pass through but the Dopa Decarboxylase Inhibitor cannot
Early PD treatment:
- increase DA production with L-DOPA (Levidopa)
- mimic action via Dopamine agonists
- decrease breakdown via MAO-B inhibitors (monoamine oxidase B)
Late PD treatment:
- cannot use L-DOPA because the amount needed has such severe side effects
- mimic action via dopamine agonists
- decrease breakdown via COMT or MAO-B inhibitors
- increase release and decrease reuptake via Amantadine
Deep Brain Stimulation: - electronic stimulation of > Subthalamic Nucleus (STN) > Globus Pallidus Internal (GPi) > Thalamus - maybe it works because it brings rhythm
Foetal DA neuron transplantation
